Human immunodeficiency virus (HIV) infected patients are now living longer due to potent antiretroviral therapy (ART). Despite the effectiveness of ART for systemic viral suppression, up to half of chronically HIV infected (HIV+) individuals will develop HIV associated neurocognitive disorders (HAND). Increasing efforts have focused on understanding the early pathophysiologic changes within the central nervous system (CNS) initiated during primary HIV infection (PHI, defined as the first year after HIV transmission). It remains unknown if early initiation of ART during PHI could reduce the future incidence of developing HAND. It is imperative that early biomarkers (including cerebrospinal fluid (CSF) and neuroimaging) are developed for understanding the mechanisms of crucial early events that may influence the trajectory of damage in the CNS. Previous studies of PHI have primarily been cross sectional and have focused on a limited number of PHI participants assessed by single modality. We propose a longitudinal study to assess the effects of PHI and early ART on brain structure which integrates structural neuroimaging analyses with blood and CSF measures of infection, inflammation and neurodenegeration, as well as clinical data including exposure to stimulant drugs of abuse to investigate possible mechanisms of brain injury beginning during PHI. Specifically, this study will employ structural neuroimaging methods (diffusion tensor imaging (DTI) and brain volumetrics) to study the CNS mechanisms that underlie the natural history of PHI in the CNS as well as the effects of starting ART in the early stages of infection. Based on our preliminary cross sectional analyses, we hypothesize that structural neuroimaging (DTI and brain volumetrics) will reveal progressive injury in the brain during early infection prior to ART which may be halted in subjects that initiate ART soon after seroconversion. Subjects using methamphetamine may have increased vulnerability to HIV-associated structural injury, tied to inflammation in the brain. This proposal will: (Aim 1) investigate the mechanisms of CNS injury in PHI prior to ART by temporally associating the emergence of abnormalities in structural imaging with laboratory biomarkers and neuropsychological performance. Additionally (Aim 2) we will explore the mechanisms of early ART effects in the CNS through assessment of white matter integrity and brain volumetrics over time in subjects both before and after starting ART. Our long term goal is to provide evidence for the appropriate timing of ART initiation and to evaluate the rationale of possible tailored adjunctive neuroprotective therapies to prevent HAND.